The embodiments described herein relate generally to treatments for endocrine disorders, such as diabetes or hypothyroidism, a neurological disorder, or any other disorder able to be treated with cell therapy, and more particularly, to encapsulated pancreatic islets comprising semi-permeable capsular membrane with tapered conduits.
Diabetes is a difficult disease to manage and treat. Conventionally, there are two acceptable treatment protocols for insulin-dependent diabetes mellitus (IDDDM). Pancreases/pancreatic islet transplantation provides good management of diabetes, but its adoption has been limited by the side effects of immunosuppressive drugs. Insulin injection or use of an insulin pump is less invasive and requires no immunosuppressive drugs, but, for many patients, blood glucose control is inadequate. Neither treatment is satisfactory.
Encapsulated pancreatic islets transplantation has long been considered as one of the more promising alternative treatment protocols for diabetes, wherein a thin (about 0.5 μm) semi-permeable islet encapsulation membrane was assumed to have “uniform pores” that could protect cells from immune attack and, at the same time, would allow the influx of molecules important for cell function/survival and efflux of the other desired cellular products with ease (gatekeeper model). Unfortunately, the “uniform pores” assumption was over simplified and flawed.
The capsular membrane pore size distribution (PSD) was obtained from the measurements of solute size exclusion coefficients (KSEC) with known size of solute molecules. The measured PSD did not agree with the uniform pore size distribution assumption of the gatekeeper model. As shown in FIG. 8, the membrane pore size distribution (PSD—solid line in FIG. 8) was found to have a Gaussian distribution of pore sizes. This was contrary to the gatekeeper model's assumption that there were no pores larger than cutoff (R0) for the immune system to pass through. The thin wall gatekeeper membrane thus could not provide adequate immunoprotection. The erroneous assumption led to a flawed membrane design and unsatisfactory experimental results.
To correct this flaw, a Barrier Model membrane design was developed. The Barrier Model has a thick membrane of about 25 μm with a pore size distribution cutoff (about 90% of pores are smaller than the cutoff) of about 20 nm in diameter. It allows small molecules, such as nutrients and oxygen to enter the membrane with ease. At the same time, the immune system (IgG of about 19 nm and IgM of about 49 nm) would be prevented from breaching the capsule all the way, for it would be stopped or snared by the smaller pores along the way. This is an accumulative effect—the thicker the membrane, the more effective the immunoprotection.
Based on a Statistical Mechanics random walk model, the time, Γ, for an immune system IgG to breach the membrane of a capsule with thickness, D, can be calculated as shown in the following Equation (1):
                    Γ        ∼                  3          ⁢                      τ            (                                          D                2                                            d                2                                      )                    ⁢                      (                                          (                                  1                  -                  f                                )                            f                        )                                              (        1        )            where d is the pore diameter, D2/d2 represents the total number of random walk steps needed to breach the membrane, τ is the time delay of each random walk step and its value may be extracted from solute size exclusion coefficients measurements, and f is the percentage of pores larger than the immune system.
Equation (1) suggests a Barrier model with about 25 μm in membrane thickness and about 20 nm (150 KDa) in pore size cutoff may be able to keep immune system IgG at bay for up to about 3 years. On the other hand, for a Gatekeeper model with about 0.5 μm membrane thickness and about 12 nm (about 60 KDa) in pore size cutoff, it may be able to keep IgG at bay for about 30 days.
The Barrier model has been tested in canine transplantation experiments, and the results were encouraging. It has normalized fasting blood glucose levels in nine out of nine dogs for up to two hundred and fourteen days with a single transplantation and re-transplantations were equally successful. No immunosuppressant or anti-inflammatory therapy was used or needed.
However, upon closer examination, the thick Barrier model insulin release was found to be wanting. The strength of a Barrier model is also its limitation. It offers good immunoprotection, but inadequate insulin release for two reasons. The first reason is hysteresis, wherein the capsule serves as an insulin reservoir. Like all reservoirs, it resists any sudden changes. The insulin secreted from an encapsulated islet will be held back and diluted before it can be released. This delays the insulin response to glucose challenges. The second reason is viscosity, wherein the capsular membrane is designed to prevent the immune system from entering. So, it stands to reason that the same narrow channels of the capsule may resist insulin from leaving. Together, hysteresis and viscosity effects limit the encapsulated islets' ability to respond to glucose challenges efficiently. The thicker the membrane, or the smaller the pores, the longer the insulin delay and the more limited the insulin release.
The Hagen-Poiseuille equation (Equation (2) below) can be used to estimate the insulin release under non-slip conditions:
                    Q        =                              (                                          π                ⁢                                                                  ⁢                                  d                  4                                            128                        )                    ⁢                      (                                          Δ                ⁢                                                                  ⁢                p                                            D                ⁢                                                                  ⁢                μ                                      )                                              (        2        )            where Q is the rate of mass flow, d is the channel (pore) diameter, Δp is proportional to the concentration gradient, μ, is viscosity, and D is membrane thickness.
Equations (1) and (2) have shown the dichotomous requirements of immunoprotection and mass transport on a membrane design. If the pores were to increase to improve mass transport, immunoprotection would be compromised. If the membrane thickness was to increase to improve immunoprotection, mass transport would be compromised.
If encapsulated islet transplantation is to be offered as a viable option for diabetic management in humans, encapsulated islet transplantation must be able to keep the patient healthy and encapsulated islets functioning for years, not just for months. Transplantations of encapsulated islets must be able to restore patient's health, and not just provide a short reprieve. None of the current capsular designs could meet this challenge. This was the reason why the encapsulation system has been a “could be” for the diabetes management.
Therefore, what is needed is a new capsular membrane design that can offer islet immunoprotection of a Barrier model and insulin release of a Gatekeeper, thus improving the mass transport without compromising the immunoprotection of encapsulated islets